Tristetraprolin inhibits macrophage IL-27-induced activation of antitumour cytotoxic T cell responses

• Published in: Nature communications Vol. 8; no. 1; pp. 867 - 11
• Main Authors: Wang, Qinghong, Ning, Huan, Peng, Hui, Wei, Lin, Hou, Rong, Hoft, Daniel F., Liu, Jianguo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-10-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/127/1213; 631/250/1619/554/1834/1269; 692/4028/67/580; Animals; Cancer; CD8 antigen; Cell activation; Clonal deletion; Coding; Cytokines; Cytotoxicity; Female; Gene Expression Regulation; Humanities and Social Sciences; Immunity; Interferon; Interferon-gamma - metabolism; Interleukin 27; Interleukins - metabolism; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; multidisciplinary; Receptors, Cytokine - metabolism; Reduction; Ribonucleic acid; RNA; Rodents; Science; Science (multidisciplinary); T-Lymphocytes, Cytotoxic - physiology; Tristetraprolin - metabolism; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00892-y

IFN-γ-producing cytotoxic T lymphocytes are essential for host defense against viral infection and cancer. Here we show that the RNA-binding tristetraprolin, encoded by
Zfp36
, is needed for CD8
+
T-cell production of IFN-γ in vivo. When activated in vitro, however, IFN-γ production by naive wild type and tristetraprolin-deficient CD8
+
T-cells is comparable. IL-27 is overproduced by tristetraprolin-deficient macrophages and increased systemically in tristetraprolin-deficient mice. Tristetraprolin suppresses IL-27 production by promoting p28 mRNA degradation. Importantly, deletion of IL-27 receptor WSX-1 in tristetraprolin-deficient mice (WSX-1/tristetraprolin double knockout) leads to a reduction in cytotoxic T lymphocyte numbers. Moreover, tumor growth is accelerated, not only in tristetraprolin-deficient mice after cytotoxic T lymphocyte depletion, but also in WSX-1/tristetraprolin double knockout mice, with substantial reduction in the number of tumor cytotoxic T lymphocytes. This study describes a regulatory pathway for IL-27 expression and cytotoxic T lymphocyte function mediated by tristetraprolin, contributing to regulation of antitumour immunity.
IL-27 is one of a number of cytokines that can induce antitumour CD8
+
T cell responses. Here the authors show that TTP, encoded by
Zfp36
, degrades p28 to inhibit IL-27 production by macrophages and is thereby a negative regulator of the antitumour response.